A putative adverse outcome pathway linking diesel engine exhaust with increased risks of metabolism-related diseases: A metabolomics-based molecular epidemiology study

Abstract

Little is known about how diesel engine exhaust (DEE) exposure is associated with changes in blood lipid concentrations, as well as the molecular initiating events (MIEs) and mechanisms underlying this association. The aim of this research was to determine the MIEs and key molecular events and thus construct a putative adverse outcome pathway (AOP) from DEE exposure to an increased risk of metabolism-related diseases by integrating occupational epidemiology and metabolomics analyses. We recruited 136 participants with high DEE exposure and 99 healthy controls to investigate the associations between polycyclic aromatic hydrocarbons (PAHs; an exposure biomarker of DEE), blood lipids (high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol), and plasma metabolites. Our results revealed that the concentrations of six OH-PAHs were increased significantly in urine samples from participants with high DEE exposure (P ≤ 0.001), and that 9-hydroxyphenanthrene (9-OHPh) is uniquely associated with decreased HDL-C concentrations (P = 0.034). Each 10 % increase in the 9-OHPh concentration corresponded to a 0.225 % decrease in the HDL-C concentration. Targeted metabolomics analysis revealed key pathways associated with both 9-OHPh and HDL-C, including alanine and glutamine metabolism, glutathione biosynthesis, sirtuin, and TP53 pathway. Additionally, nine metabolites (e.g. glutamate, glutamine, and glutathione) were enriched in pathways associated with both 9-OHPh and HDL-C. Bioinformatic analyses of these metabolites identified potential MIEs (e.g. CPT1B, LDHB, and SIX1) and adverse outcomes (liver damage, renal necrosis, and cardiac damage). Based on these findings, we propose for the first time a putative AOP connecting DEE exposure with metabolism-related disease risks, which is driven by alterations in MIEs, subsequent metabolic disturbances, and reduced HDL-C levels, thus providing crucial insights into environmental contributors to metabolic disorders.